Epithelioid hemangioendothelioma (EHE) is a rare, low-grade malignant vascular tumor that can arise regionally or systemically. Lesions are frequently found in bone, lung, liver, soft tissue, and skin  . Most EHE patients are asymptomatic at the time of the diagnosis, but as the disease advances, severe burning pain is the most common symptom . Currently, various therapies, including drug treatment  , interventional therapy , radiotherapy , and surgical treatment  have been described, however, none of these therapies can completely cure this disease, and pain may become more and more refractory . Morphine is a strong analgesic which has been used for releasing acute or chronic pain for a long time . Previous studies have reported that the dose of morphine is determined based on its effect and there is no defined ceiling dosage . Here, we report a case of systemic multiple EHE that underwent prolonged ultrahigh doses of intravenous morphine without significant signs of addiction.
2. Case Overview
In August 2013, a 13-year-old man presented to the hospital with the left knee pain after a long walk. His medical and family history revealed no major medical problems. Multiple bone tumors of lower extremity was diagnosed with X-ray examination, after that both multiple body Computed Tomography (CT) and Magnetic Resonance (MR) scan revealed systemic multiple tumors in both lungs and the left third costal (Figure 1), in the right lobe of the liver (Figure 2), the lower section of the left distal femur (Figure 3), the left proximal fibula (Figure 4) and tibia (Figure 5), and the right proximal fibula (Figure 6). A fibula biopsy was administered, and the pathological diagnosis was EHE (Figure 7). Because previous studies had reported cases in which no therapy was administered that patients survived up to 27 years  , the patient was not treated, and did not show severe pain or other discomfort related to the tumor in the following 4 years.
In January 2017, the patient appeared with intermittent pain in the left chest wall. A resection of the rib where the tumor located was carried out after the next six months, and the postoperative pathology was undoubtedly diagnosed as EHE (Figure 8). However, the intermittent pain did not disappear but turned into persistent pain. In July 2017, a dose of morphine (Morphine Hydrochloride Injection, batch number: 170602-1, NORTHEAST PHARM, Shenyang, China) 10 - 20 mg was added into a patient controlled intravenous analgesia (PCIA)
Figure 1. Tumors in both lungs and in the left third costal. CT scans showed multiple metastatic lesions of both lungs, and bone destruction of the left third anterior costal.
Figure 2. Tumors in the liver. CT scans showed metastatic lesions in the right lobe of the liver.
Figure 3. Tumor in the left distal femur. MR scans showed multiple transarticular osteolytic damages in the lower section of the left femur.
Figure 4. Tumor in the left proximal fibula. MR displayed a medullary lesion with irregular contours and osseous invasion, and an inhomogeneous signal with diffuse post contrast enhancement in the left proximal fibula.
Figure 5. Tumor in the left proximal tibia. MR showed slightly long T1 and long T2 in the upper section of the left proximal tibia, and the lesion showed obvious enhancement, and long T2 edema signals in the adjacent medullary cavity and muscle tissue.
Figure 6. Tumor in the right proximal fibula. MR scans showed osteolytic damage and osseous invasion in the right proximal fibula.
Figure 7. Histopathology of the fibula biopsy. A low-power view demonstrated irregular mesenchymal lesions, distributed in viscous liquid samples or become transparent.
Figure 8. Histopathology of the costal biopsy. A low-power view showed the neoplasm was mainly composed of a mixed proliferation of epithelioid cells and spindle cells some epithelioid cells exhibited clear intracytoplasmic.
device (diluted with normal saline to 150 ml, with a loading dose of 2 ml, a background dose of 3 ml, and an unit additional dose of 3 ml per 15 min), in that case, the intensity of analgesia was sufficient for two days, but caused side effects such as dizziness, stomach upset, nausea, and itching. However, the pain aggravated rapidly in 2 weeks, the pain score was evaluated every other day, basically the dosage of morphine increased 10 mg each time at the same volume, and the daily dosage of morphine gradually increased to 120 - 200 mg in the second month. Despite this increased dose, the patient still complained of mild pain, and could not sleep properly, although he no longer appeared to have nausea or itching. In the third month, the doctors added chlorpromazine 25 mg (12.5 mg orally in the morning, another 12.5 mg intravenously in the evening) and carbamazepine 200 mg (100 mg orally per 12 h) every day to prevent a rapid rise in the amount of morphine administered. However, the daily dose of morphine still increased quickly to meet the patient’s needs for analgesia, the pain score was assessed every day, and the dosage of morphine increased 10 mg per day on average.
In the early November 2017, the daily amount of morphine had risen to 1000 mg (1000 mg morphine diluted to 150 ml into a PCIA device, parameters set to a loading dose of 3 ml, a background dose of 5 ml, and a unit dose of 3 ml per 15 min). An opioid tolerance (OT) was diagnosed, and opioid addiction and withdrawal tests were conducted. For example, in the Addiction Severity Index Questionnaire , the patient’s rating scale was only 1 score and the interviewer severity rating got 2 points, indicated that the patient was not addictive. In the Prescription Opioid Addiction Treatment Study , result showed that the patient did not need to be treated for addiction. In the Opioid Withdrawal Scale , the patient was mental balance, only presented severe pain in the whole body without other symptoms such as sanity disorder or fidgety. In this case, a patient controlled epidural analgesia (PCEA) device was inserted to the 6/7 segment of the thoracic spine, and a dose of morphine 200 mg and ropivacaine 200 mg were administered via an epidural catheter (diluted to 150 ml, with a background dose of 3 ml, and an unit dose of 3 ml per 15 min). This provided adequate pain relief for more than one week, and the daily dosage of intravenous morphine dropped to about 800 mg. However, opioid-induced hyperalgesia (OIH) was diagnosed at the second week after the implantation of the PCEA, we started to increase the dose of epidural morphine for 10 mg every day, but that could not effectively relieve the pain from lower limbs. Subsequently, the intravenous morphine dose started to rise again (almost 20 mg/day for addition). At the beginning of the fifth month, the daily total amount of morphine administered reached 1500 mg (venous 1100 mg and epidural 400 mg on average), but still could not effectively relieve the pain. Since ongoing tests continuously excluded the possibility of addiction, an extra single intravenous injection of morphine 100 mg (basically once every 8 h) was given whenever both PCIA and PCEA could not provide sufficient analgesia.
The patient died from multiple organ failure (MOF) in late December 2017. Although he was very weak in the last days, he did not complain of pain. The total dosage of all analgesics administered was: morphine 92,530 mg, chlorpromazine 2525 mg, carbamazepine 19,200 mg, and ropivacaine 14,200 mg within 164 days (Table 1).
Surgical resection is one of the effective ways to treat EHE  . It is reported that the 5-year survival rate after surgical excision is approximately 75% , and this provides a good basis for patients to choose surgical treatment. However, complete resection is impossible in patients with systemic multiple EHE, and surgery cannot radically cure the pain . In this report, the patient was symptom-free for 4 years; although the surgery removed the pain of the lesion sites, it did not solve the patient’s pain symptoms. On the contrary, the operation caused the peripheral sensitization of pain and aggravated the progress of obstinate pains. In this condition, the palliative therapy was determined, but
Table 1. Monthly table of the drugs administration.
first of all, it was very important to use an effective measure to deal with pain that could positively affect the quality of life of the patient.
It is well-recognized that morphine is the safest and most effective analgesic for releasing chronic, cancer pain, and there is no ceiling effect . Though extended exposure to morphine can lead to some drug-related adverse reactions such as analgesic tolerance, drug addiction, hyperalgesia, etc., a research suggests that long-term, high-dose morphine use was well-tolerated, and could improve patient’s life quality without affecting life expectancy . In a nine-month study, Chatham  reported that a daily dose of morphine over 1200 mg was safe. Moreover, Lin  found that morphine could also induce the apoptosis of cancer cells in a chronic high-dose morphine treatment study, and this effect was beneficial to patient recovery. Thus, we defined the dose of morphine according to the patient’s need. In this case, the initial application of morphine was directly prescribed by the anesthesiologist. But with the aggravation of patients’ pain, our anesthesia department was unable to provide sufficient amount of morphine, thus the anesthesiologist communicated with the patient’s chief physician every morning after pain assessment, and informed the doctor in charge of the expected morphine of the day. The nurse on duty went to the pharmacy to receive the medicine with the red prescription, then told the anesthesiologist to give analgesic treatment and psychotherapy.
Currently, both OT and OIH are common in patients receiving long-term opioid management for cancer pain. OT is defined as a physiological state in which the body adapts to the medication after frequent exposure and requires higher doses to achieve the same effect. OIH is a phenomenon of enhanced pain sensitization to stimulation . The mechanisms responsible for OT and OIH are complicated, including mesenchymal stem cells attenuation, glutamate release in the spinal cord, descending facilitation, etc.   . Drugs such as cyclooxygenase-2 inhibitors, ketamine, and dextromethorphan have been proposed to help manage OIH  , but there are anxieties about the potential organ damages caused by these medicines. To reduce the interactions among a variety of drugs, and to acquire an accurate estimation of analgesia addiction, we did not add other medications to deal with these complications.
Addiction is another common adverse reaction after long-term opioid treatment. Addicted patients usually exhibit drug-seeking behavior due to depression or anxiety . The activation of the mesolimbic dopaminergic pathway, the inflammation and degeneration of neurons, including long-term potentiation and long-term depression of the glutamatergic synapses are thought to be contributed to the development of addiction  . Since our patient was always clear in consciousness, and did not appear any abnormal features suggestive of addiction, we concluded that the amount of morphine should not be limited under strict addiction assessments.
In summary, our practice represents a prolonged ultrahigh dose of morphine used in a systemic multiple EHE patient without addiction. But more case series or comparative studies are needed to evaluate the outcome of this approach, and a well-constructed evaluation scale such as the limits of OT and OIH should be adopted to assess the potential complications as well.
We would like to thank the Journal of Zhejiang University English Polishing Service for help with English use during manuscript preparation.
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